Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to new pharmaceutical compounds, pharmaceutical compositions containing these compounds, and their use to modulate the activity of the G-protein-coupled receptor, GPR1 19.
• Diabetes mellitus are disorders in which high levels of blood glucose occur as a consequence of abnormal glucose homeostasis.
• the most common forms of diabetes mellitus are Type I (also referred to as insulin-dependent diabetes mellitus) and Type II diabetes (also referred to as non-insulin-dependent diabetes mellitus).
• Type II diabetes accounting for roughly 90% of all diabetic cases, is a serious progressive disease that results in microvascular complications (including retinopathy, neuropathy and
• nephropathy as well as macrovascular complications (including accelerated
• Sitagliptin a dipeptidyl peptidase IV inhibitor
• Sitagliptin is a new drug that increases blood levels of incretin hormones, which can increase insulin secretion, reduce glucagon secretion and have other less well characterized effects.
• sitagliptin and other dipeptidyl peptidases IV inhibitors may also influence the tissue levels of other hormones and peptides, and the long-term consequences of this broader effect have not been fully investigated.
• insulin resistance may be due to reduced numbers of cellular insulin receptors, disruption of cellular signaling pathways, or both.
• the beta cells compensate for insulin resistance by increasing insulin output.
• the beta cells become unable to produce sufficient insulin to maintain normal glucose levels (euglycemia), indicating progression to Type II diabetes.
• fasting hyperglycemia occurs due to insulin resistance combined with beta cell dysfunction.
• beta cell defect dysfunction There are two aspects of beta cell defect dysfunction: 1 ) increased basal insulin release (occurring at low, non-stimulatory glucose concentrations), which is observed in obese, insulin-resistant pre-diabetic stages as well as in Type II diabetes, and 2) in response to a hyperglycemic challenge, a failure to increase insulin release above the already elevated basal level, which does not occur in pre-diabetic stages and may signal the transition from normo-glycemic insulin-resistant states to Type II diabetes.
• Current therapies to treat the latter aspect include inhibitors of the beta-cell ATP-sensitive potassium channel to trigger the release of endogenous insulin stores, and administration of exogenous insulin. Neither achieves accurate normalization of blood glucose levels and both carry the risk of eliciting hypoglycemia.
• agonist modulators of novel, similarly functioning, beta-cell GPCRs would also stimulate the release of endogenous insulin and promote normalization of glucose levels in Type II diabetes patients. It has also been shown that increased cAMP, for example as a result of GLP-1 stimulation, promotes beta-cell proliferation, inhibits beta- cell death and, thus, improves islet mass. This positive effect on beta-cell mass should be beneficial in Type II diabetes where insufficient insulin is produced.
• metabolic diseases have negative effects on other physiological systems and there is often co-occurrence of multiple disease states (e.g., Type I diabetes, Type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia,
• new GPR 1 19 modulators have been discovered. These compounds include 1 -methylcyclopropyl (3R,4R)-3-fluoro-4-( ⁇ 5- methyl-6-[(2-methylpyridin-3-yl)oxy]pyrimidin-4-yl ⁇ oxy)piperidine-1-carboxylate and 1- methylcyclopropyl (3S,4S)-3-fluoro-4-( ⁇ 5-methyl-6-[(2-methylpyridin-3-yl)oxy]pyrimidin- 4-yl ⁇ oxy)piperidine-1-carboxylate, and mixtures thereof and pharmaceutically
• These compounds modulate the activity of the G-protein-coupled receptor. More specifically the compounds modulate GPR1 19. As such, said compounds are useful for the treatment of diseases, such as diabetes, in which the activity of GPR1 19 contributes to the pathology or symptoms of the disease.
• Type I diabetes mellitus Type II diabetes mellitus
• idiopathic Type I diabetes Type lb
• latent autoimmune diabetes in adults LADA
• EOD early-onset Type 2 diabetes
• YOAD youth-onset atypical diabetes
• MODY maturity onset diabetes of the young
• malnutrition-related diabetes gestational diabetes, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction (e.g. necrosis and apoptosis),
• dyslipidemia post-prandial lipemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia,
• the compounds may be used to treat neurological disorders such as Alzheimer's disease, schizophrenia, and impaired cognition.
• the compounds will also be beneficial in gastrointestinal illnesses such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, etc.
• the compounds may also be used to stimulate weight loss in obese patients, especially those afflicted with diabetes.
• a further embodiment of the invention is directed to pharmaceutical compositions containing a compound of this invention.
• Such formulations will typically contain a compound of this invention in admixture with at least one pharmaceutically acceptable excipient.
• Such formulations may also contain at least one additional pharmaceutical agent. Examples of such agents include anti-obesity agents and/or anti-diabetic agents. Additional aspects of the invention relate to the use of the compounds of this invention in the preparation of medicaments for the treatment of diabetes and related conditions as described herein.
• a. "therapeutically effective amount” means an amount of a compound of the
• present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein;
• patient refers to warm blooded animals such as, for example, guinea pigs, mice, rats, gerbils, cats, rabbits, dogs, monkeys, chimpanzees, and humans; "treat” embraces both preventative, i.e., prophylactic, and palliative treatment, i.e., relieve, alleviate, or slow the progression of the patient's disease (or condition) or any tissue damage associated with the disease;
• modulated refers to the activation of the G-protein-coupled receptor GPR1 19 with compounds of the present invention
• pharmaceutically acceptable indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith,
• salts is intended to refer to pharmaceutically acceptable salts and to salts suitable for use in industrial processes, such as the preparation of the compound, “pharmaceutically acceptable salts” is intended to include pharmaceutically acceptable acid addition salts”.
• “pharmaceutically acceptable acid addition salts” is intended to apply to any nontoxic organic or inorganic acid addition salt of the base compounds or any of its intermediates.
• Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate.
• Illustrative organic acids, which form suitable salts include the mono-, di-, and tricarboxylic acids.
• Such acids are for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxy-benzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid, and sulfonic acids such as methane sulfonic acid and 2-hydroxyethane sulfonic acid.
• Such salts can exist in either a hydrated or substantially anhydrous form. In general, the acid addition salts of these compounds are soluble in water and various hydrophilic organic solvents.
• Stereoisomer refers to compounds that possess one or more chiral centers and each center may exist in the R or S configuration. Stereoisomers includes all diastereomeric, enantiomeric and epimeric forms as well as racemates and mixtures thereof. "Geometric isomer” refers to compounds that may exist in cis, trans, anti, syn,
• E
• Z
• Certain of the compounds of this invention may exist as geometric isomers. The compounds may possess one or more asymmetric centers, thus existing as two, or more, stereoisomeric forms. The present invention includes all the individual
• stereoisomers and geometric isomers of the compounds of this invention and mixtures thereof can be obtained by chiral separation or using the relevant enantiomer in the synthesis. As noted above, some of the compounds exist as isomers. These isomeric mixtures can be separated into their individual isomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers and
• an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
• Enantiomers can also be separated by use of a chiral HPLC column.
• the specific stereoisomers may be synthesized by using an optically active starting material, by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one stereoisomer into the other by asymmetric transformation.
• the present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 31 P, 32 P, 35 S, 18 F, 123 l, 125 l and 36 CI, respectively.
• Certain isotopically-labeled compounds of the present invention are useful in compound and/or substrate tissue distribution assays.
• Certain isotopically labeled ligands including tritium, 14 C, 35 S and 125 l could be useful in radioligand binding assays.
• Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
• isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
• Positron emitting isotopes such as 15 0, 13 N, 11 C, and 18 F are useful for positron emission tomography (PET) studies to examine receptor occupancy.
• Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non- isotopically labeled reagent.
• Polymorphs may be prepared by crystallization under various conditions, for example, using different solvents or different solvent mixtures for recrystallization; crystallization at different temperatures; and/or various modes of cooling, ranging from very fast to very slow cooling during
• Polymorphs may also be obtained by heating or melting the compound of the present invention followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
• the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
• the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
• the compounds may also exist in one or more crystalline states, i.e. as co-crystals, polymorphs, or they may exist as amorphous solids. All such forms are encompassed by the invention and claims.
• the composition further includes at least one additional pharmaceutical agent selected from the group consisting of an anti-obesity agent and an anti-diabetic agent.
• Example anti-obesity agents include dirlotapide, mitratapide, implitapide, R56918 (CAS No. 403987), CAS No. 913541-47-6, lorcaserin, cetilistat, PYY3-36, naltrexone, oleoyl-estrone, obinepitide, pramlintide, tesofensine, leptin, liraglutide, bromocriptine, orlistat, exenatide, AOD-9604 (CAS No.
• Example anti-diabetic agents include metformin, acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, tolbutamide, tendamistat, trestatin, acarbose, adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, salbostatin, balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone, troglitazone, exendin-3, exendin-4, trodusquemine, reservatrol, hyrtiosal extract, dapagl
• the compounds or compositions of this invention may be administered in an effective amount for treating a condition selected from the group consisting of hyperlipidemia, Type I diabetes, Type II diabetes mellitus, idiopathic Type I diabetes (Type lb), latent autoimmune diabetes in adults (LADA), early-onset Type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction (e.g.
• ITT impaired glucose tolerance
• conditions of impaired fasting plasma glucose metabolic acidosis, ketosis, arthritis, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertrygliceridemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcerations and ulcerative colitis, endothelial dysfunction and impaired vascular compliance,
• the method further includes administering a second composition comprising at least one additional pharmaceutical agent selected from the group consisting of an anti-obesity agent and an anti-diabetic agent, and at least one pharmaceutically acceptable excipient.
• This method may be used for admistering the compositions simultaneously or sequentially and in any order.
• the compounds of this invention are useful in the manufacture of a medicament for treating a disease, condition or disorder that modulates the activity of G-protein-coupled receptor GPR1 19. Furthermore, the compounds are useful in the preparation of a medicament for the treatment of diabetes or a morbidity associated with said diabetes.
• Suitable amino-protecting groups include acetyl, trifluoroacetyl, /-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9- fluorenylmethyleneoxycarbonyl (Fmoc).
• a "hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
• Suitable hydroxyl-protecting groups include for example, allyl, acetyl, silyl, benzyl, para-methoxybenzyl, trityl, and the like. The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.
• some of the compounds of this invention are acidic and they form salts with pharmaceutically acceptable cations.
• Some of the compounds of this invention are basic and form salts with pharmaceutically acceptable anions. All such salts are within the scope of this invention and they can be prepared by conventional methods such as combining the acidic and basic entities, usually in a stoichiometric ratio, in either an aqueous, non-aqueous or partially aqueous medium, as appropriate.
• the salts are recovered either by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization, as appropriate.
• the compounds are obtained in crystalline form according to procedures known in the art, such as by dissolution in an appropriate solvent(s) such as ethanol, hexanes or water/ethanol mixtures.
• Compounds of the present invention modulate the activity of G-protein-coupled receptor GPR1 19.
• said compounds are useful for the prophylaxis and treatment of diseases, such as diabetes, in which the activity of GPR1 19 contributes to the pathology or symptoms of the disease.
• another aspect of the present invention includes a method for the treatment of a metabolic disease and/or a metabolic-related disorder in an individual which comprises administering to the individual in need of such treatment a therapeutically effective amount of a compound of the invention, a salt of said compound or a pharmaceutical composition containing such compound.
• the metabolic diseases and metabolism-related disorders are selected from, but not limited to, hyperlipidemia, Type I diabetes, Type II diabetes mellitus, idiopathic Type I diabetes (Type lb), latent autoimmune diabetes in adults (LADA), early-onset Type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction (e.g. necrosis and apoptosis),
• dyslipidemia post-prandial lipemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertrygliceridemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcerations, endothelial dysfunction, hyper apo B lipoproteinemia and impaired vascular compliance.
• ITT impaired glucose tolerance
• the compounds may be used to treat neurological disorders such as Alzheimer's disease, schizophrenia, and impaired cognition.
• the compounds will also be beneficial in gastrointestinal illnesses such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, etc.
• the compounds may also be used to stimulate weight loss in obese patients, especially those afflicted with diabetes.
• the present invention further provides a method for preventing or ameliorating the symptoms of any of the diseases or disorders described above in a subject in need thereof, which method comprises administering to a subject a therapeutically effective amount of a compound of the present invention.
• Further aspects of the invention include the preparation of medicaments for the treating diabetes and its related co-morbidities.
• the compounds need to be administered in a quantity sufficient to modulate activation of the G-protein- coupled receptor GPR1 19. This amount can vary depending upon the particular disease/condition being treated, the severity of the patient's disease/condition, the patient, the particular compound being administered, the route of administration, and the presence of other underlying disease states within the patient, etc.
• the compounds When administered systemically, the compounds typically exhibit their effect at a dosage range of from about 0.1 mg/kg/day to about 100 mg/kg/day for any of the diseases or conditions listed above. Repetitive daily administration may be desirable and will vary according to the conditions outlined above.
• the compounds of the present invention may be administered by a variety of routes. They may be administered orally. The compounds may also be administered parenterally (i.e., subcutaneously, intravenously, intramuscularly, intraperitoneally, or intrathecally), rectally, or topically.
• the compounds of this invention may also be used in conjunction with other pharmaceutical agents for the treatment of the diseases, conditions and/or disorders described herein. Therefore, methods of treatment that include administering compounds of the present invention in combination with other pharmaceutical agents are also provided.
• Suitable pharmaceutical agents that may be used in combination with the compounds of the present invention include anti-obesity agents (including appetite suppressants), anti-diabetic agents, anti-hyperglycemic agents, lipid lowering agents, and anti-hypertensive agents.
• Suitable anti-diabetic agents include an acetyl-CoA carboxylase- (ACC) inhibitor such as those described in WO2009144554, WO2003072197, WO2009144555 and WO2008065508, a diacylglycerol O-acyltransferase 1 (DGAT-1 ) inhibitor, such as those described in WO09016462 or WO2010086820, AZD7687 or LCQ908, diacylglycerol O- acyltransferase 2 (DGAT-2) inhibitor, monoacylglycerol O-acyltransferase inhibitors, a phosphodiesterase (PDE)-10 inhibitor, an AMPK activator, a sulfonylurea (e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquid
• GSK1362885 a VPAC2 receptor agonist
• SGLT2 inhibitors such as those described in E.C. Chao et al. Nature Reviews Drug Discovery 9, 551-559 (July 2010) including dapagliflozin, canagliflozin, BI-10733, tofogliflozin (CSG452), ASP-1941 , THR1474, TS-071 , ISIS388626 and LX421 1 as well as those in WO2010023594, a glucagon receptor modulator such as those described in Demong, D.E. et al.
• GPR1 19 modulators particularly agonists, such as those described in WO2010140092, WO2010128425, WO2010128414, WO2010106457, Jones, R.M. et al. in Medicinal Chemistry 2009, 44, 149-170 (e.g. MBX-2982, GSK1292263, APD597 and PSN821 ), FGF21 derivatives or analogs such as those described in Kharitonenkov, A. et al.
• TGR5 also termed GPBAR1
• GPBAR1 GPBAR1 receptor modulators
• agonists such as those described in Zhong, M., Current Topics in Medicinal Chemistry, 2010, 10(4), 386-396 and INT777
• GPR40 agonists such as those described in Medina, J.C., Annual Reports in Medicinal
• anti-diabetic agents include metformin and DPP-IV inhibitors (e.g., sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin).
• antidiabetic agents could include inhibitors or modulators of carnitine palmitoyi transferase enzymes, inhibitors of fructose 1 ,6-diphosphatase, inhibitors of aldose reductase, mineralocorticoid receptor inhibitors, inhibitors of TORC2, inhibitors of CCR2 and/or CCR5, inhibitors of PKC isoforms (e.g.
• PKCa ⁇ , PKCy
• inhibitors of fatty acid synthetase inhibitors of serine palmitoyi transferase
• suitable anti-diabetic agents include mechanisms listed by Carpino, P.A., Goodwin, B. Expert Opin. Ther. Pat, 2010, 20(12), 1627-51 .
• Suitable anti-obesity agents include 1 1 ⁇ -hydroxy steroid dehydrogenase-1 (1 1 ⁇ -HSD type 1 ) inhibitors, stearoyl-CoA desaturase-1 (SCD-1 ) inhibitor, MCR-4 agonists, cholecystokinin-A (CCK- A) agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetic agents, ⁇ 3 adrenergic agonists, dopamine agonists (such as bromocriptine), melanocyte-stimulating hormone analogs, 5HT2c agonists, melanin concentrating hormone antagonists, leptin (the OB protein), leptin analogs, leptin agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin, i.e.
• anorectic agents such as a bombesin agonist
• neuropeptide-Y antagonists e.g., NPY Y5 antagonists such as velneperit
• PYY3-36 including analogs thereof
• BRS3 modulator mixed antagonists of opiod receptor subtypes, thyromimetic agents, dehydroepiandrosterone or an analog thereof, glucocorticoid agonists or antagonists, orexin antagonists, glucagon-like peptide-1 agonists, ciliary neurotrophic factors (such as AxokineTM available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter s Gamble Company, Cincinnati, OH), human agouti-related protein (AGRP) inhibitors, histamine 3 antagonists or inverse agonists, neuromedin U agonists, MTP/ApoB inhibitors (e.g., gut-selective MTP inhibitors, such as dirlotapide, J
• Preferred anti-obesity agents for use in the combination aspects of the present invention include gut-selective MTP inhibitors (e.g., dirlotapide, mitratapide and implitapide, R56918 (CAS No. 403987) and CAS No. 913541 -47-6), CCKa agonists (e.g., N-benzyl-2-[4-(1 H-indol-3-ylmethyl)-5-oxo-1 -phenyl-4,5-dihydro-2,3, 6,10b- tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide described in PCT Publication No. WO 2005/1 16034 or US Publication No.
• CCKa agonists e.g., N-benzyl-2-[4-(1 H-indol-3-ylmethyl)-5-oxo-1 -phenyl-4,5-dihydro-2,3, 6,10b-
• 5HT2c agonists e.g., lorcaserin
• MCR4 agonist e.g., compounds described in US 6,818,658
• lipase inhibitor e.g., Cetilistat
• PYY3-36 as used herein "PYY 3 -3 6 " includes analogs, such as peglated PYY3-36 e.g., those described in US Publication 2006/0178501 ), opioid antagonists (e.g., naltrexone), oleoyl-estrone (CAS No.
• compounds of the present invention and combination therapies are administered in conjunction with exercise and a sensible diet.
• compositions which comprise a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, in admixture with at least one pharmaceutically acceptable excipient.
• compositions include those in a form adapted for oral, topical or parenteral use and can be used for the treatment of diabetes and related conditions as described above.
• compositions can be formulated for administration by any route known in the art, such as subdermal, inhalation, oral, topical, parenteral, etc.
• the compositions may be in any form known in the art, including but not limited to tablets, capsules, powders, granules, lozenges, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
• Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
• the tablets may be coated according to methods well known in normal pharmaceutical practice.
• Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
• Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats,
• emulsifying agents for example lecithin, sorbitan monooleate, or acacia
• non-aqueous vehicles which may include edible oils, for example almond oil, oily esters such as glycerin, propylene glycol, or ethyl alcohol
• preservatives for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavoring or coloring agents.
• fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred.
• the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle or other suitable solvent.
• the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
• agents such as local anesthetics, preservatives and buffering agents etc. can be dissolved in the vehicle.
• the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
• compositions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
• the compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
• a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
• the compositions may contain, for example, from about 0.1 % to about 99 by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will contain, for example, from about 0.1 to 900 mg of the active ingredient, more typically from 1 mg to 250mg.
• starting materials are generally available from commercial sources such as Aldrich Chemicals Co. (Milwaukee, Wl), Lancaster Synthesis, Inc. (Windham, NH), Acros Organics (Fairlawn, NJ), Maybridge Chemical Company, Ltd. (Cornwall, England), Tyger Scientific (Princeton, NJ), and AstraZeneca Pharmaceuticals (London, England), Mallinckrodt Baker (Phillipsburg NJ); EMD
• NMR spectra were recorded on a Varian UnityTM 400 (DG400-5 probe) or 500 (DG500-5 probe - both available from Varian Inc., Palo Alto, CA) at room temperature at 400 MHz or 500 MHz respectively for proton analysis. Chemical shifts are expressed in parts per million (delta) relative to residual solvent as an internal reference.
• the peak shapes are denoted as follows: s, singlet; d, doublet; dd, doublet of doublet; t, triplet; q, quartet; m, multiplet; bs, broad singlet; 2s, two singlets.
• Atmospheric pressure chemical ionization mass spectra were obtained on a WatersTM Spectrometer (Micromass ZMD, carrier gas: nitrogen) (available from Waters Corp., Milford, MA, USA) with a flow rate of 0.3 mL/minute and utilizing a 50:50 water/acetonitrile eluent system.
• Electrospray ionization mass spectra were obtained on a liquid chromatography mass spectrometer from WatersTM (Micromass ZQ or ZMD instrument (carrier gas: nitrogen) (Waters Corp., Milford, MA, USA) utilizing a gradient of 95:5 - 0:100 water in acetonitrile with 0.01 % formic acid added to each solvent.
• These instruments utilized a Varian Polaris 5 C18-A20x2.0mm column (Varian Inc., Palo Alto, CA) at flow rates of 1 mL/minute for 3.75 minutes or 2 mL/minute for 1 .95 minutes.
• Optical rotations were determined using a Perkin-Elmer model 343 polarimeter. Concentration in vacuo refers to evaporation of solvent under reduced pressure using a rotary evaporator.
• GPR1 19 agonist activity was determined with a cell-based assay utilizing an HTRF (Homogeneous Time-Resolved Fluorescence) cAMP detection kit (cAMP dynamic 2 Assay Kit; Cis Bio cat # 62AM4PEC) that measures cAMP levels in a HEK293-CRE beta-lactamase reporter cell line expressing human GPR1 19.
• the method is a competitive immunoassay between native cAMP produced by the cells and the cAMP labeled with the dye d2.
• the tracer binding is visualized by a Mab anti-cAMP labeled with Cryptate.
• the specific signal i.e. energy transfer
• hGPR1 19 HEK-CRE beta-lactamase cells are removed from cryopreservation and diluted in growth medium (Dulbecco's modified Eagle medium high glucose (DMEM; Gibco Cat # 1 1995-065), 1 % charcoal dextran treated fetal bovine serum (CD serum; HyClone Cat # SH30068.03), 1x MEM
• Nonessential amino acids (Gibco Cat # 15630-080) and 25 mM HEPES pH 7.0 (Gibco Cat # 15630-080)).
• the cell concentration was adjusted to 1 .5 x 10 5 cells/mL and 30 mLs of this suspension was added to a T-175 flask and incubated at 37 degrees Celsius in a humidified environment in 5% carbon dioxide.
• the cells were removed from the T-175 flask (by rapping the side of the flask), centrifuged at 800 x g and then re-suspended in assay medium (1 x HBSS +CaCI 2 + MgCI 2 (Gibco Cat # 14025-092) and 25 mM HEPES pH 7.0 (Gibco Cat # 15630-080)).
• assay medium (1 x HBSS +CaCI 2 + MgCI 2 (Gibco Cat # 14025-092) and 25 mM HEPES pH 7.0 (Gibco Cat # 15630-080)
• Varying concentrations of each compound to be tested were diluted in assay buffer containing 3-isobutyl-1 -methylxanthin (IBMX; Sigma cat # I5879) and added to the assay plate wells in a volume of 2 microL (final IBMX concentration was 400 microM and final DMSO concentration was 0.58%). Following 30 minutes incubation at room temperature, 5 microL of labeled d2 cAMP and 5 microL of anti-cAMP antibody (both diluted 1 :20 in cell lysis buffer; as described in the manufacturers assay protocol) were added to each well of the assay plate.
• IBMX 3-isobutyl-1 -methylxanthin
• the intrinsic activity is the percent of maximal activity of the test compound, relative to the activity of a standard GPR1 19 agonist, 4-[[6-[(2-fluoro-4 methylsulfonylphenyl) amino]pyrimidin-4-yl]oxy]piperidine-1 -carboxylic acid isopropyl ester (WO2005121 121 ), or (S)-1-methylcyclopropyl 4-(1 -fluoro-2-(2-(2,3,6- trifluorophenyl)acetamido)ethyl)piperidine-1 -carboxylate (see Figure below; disclosed in Bioorganic & Medicinal Chemistry Letters 2011 , 21, 1306-1309), at a final concentration of 10 micromolar.
• a 1 L flask was charged with titanium methoxide (100 g), cyclohexanol (232 g), and toluene (461 ml_). The flask was equipped with a Dean-Stark trap and condenser. The mixture was heated at 140 degrees Celsius until the methanol was removed. The toluene was removed at 180 degrees Celsius. More toluene was added and this process was repeated twice. After all the toluene was removed the flask was dried under high vacuum. Diethyl ether (580 mL) was added to the flask to prepare a 1 M solution in diethyl ether.
• a 5 L, 3-neck flask was equipped with an overhead stirrer, inert gas inlet and a pressure-equalizing addition funnel.
• the flask was flushed with nitrogen gas and charged with methyl acetate (60.1 mL, 756 mmol), titanium cyclohexyloxide (1 M solution in ether 75.6 mL), and diethyl ether (1500 mL).
• the solution was stirred while keeping the reaction flask in a room temperature water bath.
• the addition funnel was charged with the 3 M ethylmagnesium bromide solution (554 mL, 1 .66 moles).
• the Grignard reagent was added drop-wise over 3 hours at room temperature.
• a 2000 mL 4-neck flask was equipped with a mechanical stirrer, inert gas inlet, thermometer, and two pressure - equalizing addition funnels.
• the flask was flushed with nitrogen and charged with 490 mL of diethyl ether followed by 18.2 mL (30 mmol) of titanium tetra(2-ethylhexyloxide).
• One addition funnel was charged with a solution prepared from 28.6 mL (360 mmol) of methyl acetate diluted to 120 mL with ether.
• the second addition funnel was charged with 200 mL of 3 M ethylmagnesium bromide in ether solution.
• the reaction flask was cooled in an ice water bath to keep the internal temperature at 10 degrees Celsius or below. Forty milliliters of the methyl acetate solution was added to the flask.
• the Grignard reagent was then added drop-wise from the addition funnel at a rate of about 2 drops every second, and no faster than 2 mL per minute. After the first 40 mL of Grignard reagent had been added, another 20 mL portion of methyl acetate in ether solution was added. After the second 40 mL of Grignard reagent had been added, another 20 mL portion of methyl acetate in diethyl ether solution was added.
• the mixture was stirred for an additional 15 minutes following the completion of the addition of Grignard reagent.
• the mixture was then poured into a mixture of 660 g of ice and 60 mL of concentrated sulfuric acid with rapid stirring to dissolve all solids.
• the phases were separated and the aqueous phase was extracted again with 50 mL of diethyl ether.
• the combined ether extracts were washed with 15 mL of 10% aqueous sodium carbonate, 15 mL of brine, and dried over 30 grams magnesium sulfate for 1 hour with stirring.
• the ether solution was then filtered. Tri-n-butylamine (14.3 mL, 60 mmol) and mesitylene (10 mL were added.
• the aqueous layer was extracted twice with ethyl acetate, and all the organic layers were combined and washed sequentially with saturated aqueous sodium bicarbonate and brine and then dried over magnesium sulfate. The mixture was filtered, and the filtrate was
• Step B can be performed as follows, isolating the hydrate of the ketone.
• ieri-butyl-4-[(trimethylsilyl)oxy]-3,6-dihydropyridine-1 (2H)- carboxylate 41 .3 g, 0.15 mol
• acetonitrile 500 mL
• SelectfluorTM 56.9 g, 0.16 mol
• the resulting pale yellow suspension was stirred at room temperature for 4 hours 10 minutes. Saturated aqueous sodium bicarbonate and ethyl acetate were added, and the layers were separated.
• the aqueous layer was extracted twice with ethyl acetate, and all the organic layers were combined and washed sequentially with saturated aqueous sodium bicarbonate and brine and then dried over magnesium sulfate. The mixture was filtered, and the filtrate was
• Step C can be performed starting with the hydrate tert-butyl 3-fluoro-
• pH 7 phosphate buffer 150 mL
• a 35% aqueous hydrogen peroxide solution 150 mL
• the resulting mixture was stirred for 30 minutes and diluted with ethyl acetate.
• the organic layer was separated and sequentially with water, saturated aqueous sodium thiosulfate and brine.
• a 1 gram sample of racemic ieri-butyl-(3,4-c/ ' s)-3-fluoro-4-hydroxy-piperidine-1 - carboxylate was purified into its enantiomers via preparatory high pressure liquid chromatography utilizing a Chiralpak AD-H column (10 x 250 mm) with a mobile phase of 90:10 carbon dioxide and ethanol respectively at a flow rate of 10 mL/minute.
• the wavelength for monitoring the separation was 210 nm.
• the analytical purity of each enantiomer was determined using analytical high pressure chromatography using a Chiralpak AD-H (4.6 mm x 25 cm) column with an isocratic mobile phase of 90:10 carbon dioxide and ethanol respectively at a flow rate of 2.5 mL/minute.
• the wavelength for monitoring the peaks was 210 nm.
• the following two isomers were obtained:
• a 1 .1 gram sample of racemic te/t-butyl (3,4-/rans)-3-fluoro-4-( ⁇ 5-methyl-6-[(2- methylpyridin-3-yl)oxy]pyrimidin-4-yl ⁇ oxy)piperidine-1 -carboxylate was purified into its enantiomers via preparatory high pressure liquid chromatography utilizing a Chiralcel OD-H column (10 x 250 mm) with a mobile phase of 90:10 carbon dioxide and ethanol respectively at a flow rate of 10 mL/minute with a loading of 5.5 mg/injection.
• the wavelength for monitoring the separation was 210 nm.
• the title compound was prepared from terf-butyl (3S,4S)-3-fluoro-4-hydroxypiperidine-1- carboxylate (Enantiomer 2 from above) (20 mg, 0.09 mmol) and (2S)-3,3,3-trifluoro-2- methoxy-2-phenylpropanoyl chloride (34 ⁇ _, 0.18 mmol) in a manner similar to that used to prepare tert-butyl (3S,4S)-3-fluoro-4- ⁇ [(2S)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]oxy ⁇ piperidine-1 -carboxylate.
• the title compound was obtained as a clear, colorless, viscous residue (41 mg, 100%).
• the title compound was prepared from terf-butyl (3S,4S)-3-fluoro-4-( ⁇ 5-methyl-6-[(2- methylpyridin-3-yl)oxy]pyrimidin-4-yl ⁇ oxy)piperidine-1-carboxylate (550 mg, 1 .32 mmol) in a manner similar to that used to prepare 4- ⁇ [(3f?,4/ : ?)-3-fluoropiperidin-4-yl]oxy ⁇ -5- methyl-6-[(2-methylpyridin-3-yl)oxy]pyrimidine.
• the title compound was obtained as a white solid (374 mg, 89%).
• the title compound was prepared from 4- ⁇ [(3S,4S)-3-fluoropiperidin-4-yl]oxy ⁇ -5-methyl- 6-[(2-methylpyridin-3-yl)oxy]pyrimidine (125 mg, 0.39 mmol) in a manner similar to that used to prepare 1 -methylcyclopropyl (3f?,4f?)-3-fluoro-4-( ⁇ 5-methyl-6-[(2-methylpyridin- 3-yl)oxy]pyrimidin-4-yl ⁇ oxy)piperidine-1 -carboxylate.
• the title compound was obtained as a white solid (160 mg, 98%).

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